shu-9119 and Hyperphagia

To test the commonly held assumption that gastric bypass surgery lowers body weight because it limits the ability to eat large amounts of food.. Central melanocortin signaling was blocked by ICV infusion of the melanocortin-3/4 receptor antagonist SHU9119 for 14 days in rats whose high-fat diet-induced obesity had been reversed by Roux-en-Y gastric bypass surgery.. SHU9119 increased daily food intake (+ 100%), body weight (+30%), and fat mass (+50%) in rats with RYGB, surpassing the presurgical body weight and that of saline-treated sham-operated rats. Doubling of food intake was entirely due to increased meal frequency, but not meal size. After termination of SHU9119, body weight promptly returned to near preinfusion levels. In sham-operated rats, SHU9119 produced even larger increases in food intake and body weight.. RYGB rats do not settle at a lower level of body weight because they cannot eat more food as they can easily double food intake by increasing meal frequency. The reversible obesity suggests that RYGB rats actively defend the lower body weight. However, because both RYGB and sham-operated rats responded to SHU9119, central melanocortin signaling is not the critical mechanism in RYGB rats responsible for this defense.

Topics: Animals; Body Weight; Diet, High-Fat; Eating; Gastric Bypass; Hyperphagia; Male; Melanocortins; Melanocyte-Stimulating Hormones; Obesity; Rats; Rats, Sprague-Dawley; Receptor, Melanocortin, Type 4; Weight Loss

Changes in dietary macronutrient composition and/or central nervous system neuronal activity can underlie obesity and disturbed fuel homeostasis. We examined whether switching rats from a diet with high carbohydrate content (HC; i.e., regular chow) to diets with either high fat (HF) or high fat/high protein content at the expense of carbohydrates (LC-HF-HP) causes differential effects on body weight and glucose homeostasis that depend on the integrity of brain melanocortin (MC) signaling. In vehicle-treated rats, switching from HC to either HF or LC-HF-HP feeding caused similar reductions in food intake without alterations in body weight. A reduced caloric intake (-16% in HF and LC-HF-HP groups) required to maintain or increase body weight underlay these effects. Chronic third cerebroventricular infusion of the MC receptor antagonist SHU9119 (0.5 nmol/day) produced obesity and hyperphagia with an increased food efficiency again observed during HF (+19%) and LC-HF-HP (+33%) feeding. In this case, however, HF feeding exaggerated SHU9119-induced hyperphagia and weight gain relative to HC and LC-HF-HP feeding. Relative to vehicle-treated controls, SHU9119 treatment increased plasma insulin (2.8-4 fold), leptin (7.7-15 fold), and adiponectin levels (2.4-3.7 fold), but diet effects were only observed on plasma adiponectin (HC and LC-HF-HP

Topics: Animals; Body Composition; Body Weight; Brain; Dietary Carbohydrates; Dietary Fats; Dietary Proteins; Dose-Response Relationship, Drug; Eating; Energy Metabolism; Glucose Tolerance Test; Glycogen; Homeostasis; Hormones; Hyperphagia; Liver; Male; Melanocyte-Stimulating Hormones; Rats; Rats, Wistar; Receptors, Corticotropin; Receptors, Melanocortin; Signal Transduction

The multiple-day hyperphagic effect of the melanocortin 3/4 receptor antagonist, SHU9119, is apparently abolished when rats are food-deprived for 24 h after central (4th-ventricular) injection. Here, we affirmed this indication, and addressed the possibility that the orexigenic potency of SHU9119 is simply masked by the refeeding hyperphagia that follows food deprivation. This explanation is discounted by our finding that the drug response in ad libitum-fed rats and the deprivation response are expressed at different, and non-overlapping, times of day. We then asked whether food consumption during a hypothesized critical period in the hours after treatment is necessary for expression of the hyperphagic response to SHU9119, or alternatively, whether blood-borne signals that emerge only after an extended period of food restriction underlie the drug-state interaction. Evidence favoring the latter interpretation was derived from a series of four experiments over which the timing and duration of food access after drug administration was varied. The results indicate an interaction between melanocortin receptor activity and the metabolic state of the animal, and constrain our thinking about the peripheral signals and central mechanisms that underlie this interaction.

Topics: Animals; Circadian Rhythm; Eating; Food Deprivation; Hyperphagia; Male; Melanocyte-Stimulating Hormones; Rats; Rats, Sprague-Dawley; Receptors, Melanocortin; Time Factors

The voluntary suppression of food intake that accompanies involuntary overfeeding is an effective regulatory response to positive energy balance. Because the pro-opiomelanocortin (POMC)-derived melanocortin system in the hypothalamus promotes anorexia and weight loss and is an important mediator of energy regulation, we hypothesized that it may contribute to the hypophagic response to overfeeding. Two groups of rats were overfed to 105 and 116% of control body weight via a gastric catheter. In the first group, in situ hybridization was used to measure POMC gene expression in the rostral arcuate (ARC). Overfeeding increased POMC mRNA in the ARC by 180% relative to levels in control rats. For rats in the second group, the overfeeding was stopped, and they were infused intracerebroventricularly with SHU9119 (SHU), a melanocortin (MC) antagonist at the MC3 and MC4 receptor, or vehicle. Although SHU (0.1 nmol) had no effect on food intake of control rats, intake of overfed rats increased by 265% relative to CSF-treated controls. This complete reversal of regulatory hypophagia not only maintained but actually increased the already elevated weight of overfed rats, whereas CSF-treated overfed rats lost weight. These results indicate that CNS MCs mediate hypophagic signaling in response to involuntary overfeeding and support the hypothesis that MCs are important in the central control of energy homeostasis.

Topics: alpha-MSH; Animals; Body Weight; Brain; Eating; Hyperphagia; In Situ Hybridization; Male; Melanocyte-Stimulating Hormones; Osmolar Concentration; Pro-Opiomelanocortin; Rats; Rats, Long-Evans; RNA, Messenger